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Title of Journal: Angiogenesis

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Abbravation: Angiogenesis

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Springer Netherlands

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DOI

10.1016/0013-7944(87)90194-9

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1573-7209

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Overexpression of BMP4 inhibits experimental chor

Authors: Jing Xu Danhong Zhu Shozo Sonoda Shikun He Christine Spee Stephen J Ryan David R Hinton
Publish Date: 2012/03/04
Volume: 15, Issue: 2, Pages: 213-227
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Abstract

Bone morphorgenetic protein BMP4 has been shown to play a pivotal role in eye development however its role in mature retina or ocular angiogenic diseases is unclear Activating downstream Smad signaling BMP4 can be either proangiogenic or antiangiogenic depending on the context of cell types and associated microenvironment In this study we generated transgenic mice overexpressing BMP4 in retinal pigment epithelial RPE cells Vmd2Bmp4 Tg mice and used the laserinduced choroidal neovascularization CNV model to study the angiogenic properties of BMP4 in adult eyes Vmd2Bmp4 Tg mice displayed normal retinal histology at 10 weeks of age when compared with agematched wildtype mice Overexpression of BMP4 in RPE in the transgenic mice was confirmed by realtime PCR and immunostaining Elevated levels of Smad15 phosphorylation were found in BMP4 transgenic mice compared to wildype mice Overexpression of BMP4 was associated with less severe CNV as characterized by fluorescein angiography CNV volume measurement and histology While control mice showed increased levels of vascular endothelial growth factor VEGF and matrix metalloproteinase MMP9 after laser injury Vmd2Bmp4 Tg showed no increase in either VEGF or MMP9 Further we found that TNFinduced MMP9 secretion in vitro was reduced by pretreatment of RPE cells with BMP4 The inhibition of MMP9 was Smaddependent because BMP4 failed to repress TNFinduced MMP9 expression when Smad15 was silenced by siRNA In summary our studies identified an antiangiogenic role for BMP4 in laserinduced CNV mediated by direct inhibition of MMP9 and indirect inhibition of VEGF

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